Indoles from commensal microbiota promote mobility during aging

Abstract: Aging is associated with loss of mobility and also with dysbiosis, but it is unclear what microbiota products contribute to health or frailty. We identified indole and its derivatives as molecules secreted by benevolent commensal bacteria that act across diverse phyla (C. elegans, Drosophila, mice) to augment healthspan and allow animals to live better for longer. Our preliminary and published data suggest that as animals age, indole acts via the Aryl hydrocarbon receptor [AHR] to limit sarcopenia and maintain mobility in aged animals; specifically, indoles limit the loss of critical sarcomere proteins as well as A- and I-bands within the muscle sarcomere. Citing our work as impetus, a recent metabolomic study using samples from the Osteoporotic Fractures in Men [MrOS] cohort found that loss of indole-producing bacteria reduced plasma indole levels and correlated with decreased mobility in aged humans. We hypothesize that indole promotes stability of muscle proteins essential for the contractile apparatus by promoting chaperone-mediated refolding of damaged proteins, or by regulating proteasome activity to promote loss of irreparable proteins and/or limiting aggregation of damaged proteins. We identified another indole-regulated process in muscles that may aLect motility during aging. Specifically, indole restores youthful expression of genes associated with mitochondrial respiratory function and eLiciency that fuel muscle activity. Indole also limits mitochondrial fragmentation in aging muscle, a process associated with reduced ATP production and increased reactive oxygen species [ROS] production. We hypothesize that during aging, indole (i) regulates the proteostasis machinery, including both chaperones and the ubiquitin-proteasome system [UPS], to refold or eliminate damaged sarcomere proteins and preserve myofibrils; and (ii) upregulates mitochondria respiration and reduces ROS production, to maximize ATP production and limit damage to sarcomeres. Our Aims determine how indole limits sarcomere and mitochondrial damage, maintains muscle mass and function, and promotes mobility during aging. Aim 1 determines the mechanism by which indole limits age-dependent loss of existing assembled myofibrils via upregulating the levels of the myosin chaperone UNC-45 and the UPS. Aim 2 determines how indole maintains or improves mitochondrial function and morphology during aging to fuel muscle activity and limit ROS damage to myofibrils. Aim 3 uses genetic approaches to identify additional cellular pathways regulated by indole that promote mitochondrial or sarcomere stability and motility during aging. We use genetic and biochemical analysis in the nematode Caenorhabditis elegans, whose striated muscles exhibit significant structural conservation with mammals. Importantly, aging C. elegans exhibit loss of mobility and changes in proteostasis, including loss of the contractile apparatus and mitochondrial function, characteristic features of sarcopenia in mammals that are mitigated by indole. Here, we also propose to corroborate our worm results in aged mice. Together, these studies will provide mechanistic information on how indole derived from commensal bacteria counteracts sarcopenia during aging. These studies are essential for developing indoles as biomarkers for frailty and health, and as possible therapeutics to treat sarcopenia and other forms of muscle wasting in the elderly.